Voluntary Wheel Running Partially Attenuates Early Life Stress-Induced Neuroimmune Measures in the Dura and Evoked Migraine-Like Behaviors in Female Mice.

Olivia C Eller,Ruipeng Wang,Julie A Christianson,Gregory Dussor,Xiaofang Yang,Isabella M Fuentes,Angela N Pierce,Brittni M Jones,Aaron D Brake

doi:10.3389/fphys.2021.665732

Abstract

Migraine is a complex neurological disorder that affects three times more women than men and can be triggered by endogenous and exogenous factors. Stress is a common migraine trigger and exposure to early life stress increases the likelihood of developing chronic pain disorders later in life. Here, we used our neonatal maternal separation (NMS) model of early life stress to investigate whether female NMS mice have an increased susceptibility to evoked migraine-like behaviors and the potential therapeutic effect of voluntary wheel running. NMS was performed for 3 h/day during the first 3 weeks of life and initial observations were made at 12 weeks of age after voluntary wheel running (Exercise, -Ex) or sedentary behavior (-Sed) for 4 weeks. Mast cell degranulation rates were significantly higher in dura mater from NMS-Sed mice, compared to either naïve-Sed or NMS-Ex mice. Protease activated receptor 2 (PAR2) protein levels in the dura were significantly increased in NMS mice and a significant interaction of NMS and exercise was observed for transient receptor potential ankyrin 1 (TRPA1) protein levels in the dura. Behavioral assessments were performed on adult (>8 weeks of age) naïve and NMS mice that received free access to a running wheel beginning at 4 weeks of age. Facial grimace, paw mechanical withdrawal threshold, and light aversion were measured following direct application of inflammatory soup (IS) onto the dura or intraperitoneal (IP) nitroglycerin (NTG) injection. Dural IS resulted in a significant decrease in forepaw withdrawal threshold in all groups of mice, while exercise significantly increased grimace score across all groups. NTG significantly increased grimace score, particularly in exercised mice. A significant effect of NMS and a significant interaction effect of exercise and NMS were observed on hindpaw sensitivity following NTG injection. Significant light aversion was observed in NMS mice, regardless of exercise, following NTG. Finally, exercise significantly reduced calcitonin gene-related peptide (CGRP) protein level in the dura of NMS and naïve mice. Taken together, these findings suggest that while voluntary wheel running improved some measures in NMS mice that have been associated with increased migraine susceptibility, behavioral outcomes were not impacted or even worsened by exercise.

Highlights

Migraine is a neurological disorder that presents as throbbing cranial pain, sensitivity to light and sound, nausea, fatigue, irritability, muscle tenderness, and cutaneous allodynia (Dodick, 2018)
There was a non-significant increase in the number of mast cells counted in the neonatal maternal separation (NMS)-Sed dura (Figure 2A)
A significant overall NMS/exercise interaction effect was observed on dural mast cell degranulation, such that NMS-Sed mice had a significantly higher degranulation rate compared to either naïve-Sed or NMS-Ex mice (Figure 2B)

Summary

INTRODUCTION

Migraine is a neurological disorder that presents as throbbing cranial pain, sensitivity to light (photophobia) and sound (phonophobia), nausea, fatigue, irritability, muscle tenderness, and cutaneous allodynia (Dodick, 2018). A model of secondary traumatic stress during the neonatal period is the only published early life stress model used to study migraine, which has shown increased expression of CGRP, signal transduction proteins, and glial fibrillary acidic protein in the spinal trigeminal nucleus (Hawkins et al, 2018) and increased facial allodynia following exposure to a pungent odor (Peterson et al, 2020). Our model of early life stress in mice, using neonatal maternal separation (NMS) demonstrates urogenital hypersensitivity, increased MC degranulation in the affected organs, and reduced expression of stress-related regulatory genes in the hypothalamus and hippocampus, which is a major inhibitory regulator of the HPA axis (Pierce et al, 2014, 2016; Fuentes et al, 2017). Migraine can affect both sexes, we carried out these studies in female mice as women comprise the majority of migraineurs (Burch et al, 2018)

MATERIALS AND METHODS

RESULTS

DISCUSSION

ETHICS STATEMENT